and its clearance by the flow. In an extreme case in which aerobic metabolism is zero, the metabolic production of CO 2 (VCO 2 ) is also zero, and the venous content equals the arterial content. However, although ‘increased VCO 2 ’ cannot occur in anaerobiosis, there is no doubt that venous PCO 2 (or tissue PCO 2 from gastric tonometry) is increased during energy failure. The meaning of this phenomenon becomes clear if we consider the relationship between the CO 2 content (CvCO 2 ) and the CO 2 tension (PvCO 2 ), also called the CO 2 dissociation curve. This is reasonably linear in the PCO 2 range of 20 to 80 mmHg. However, its position is strongly influenced by the acid base status ofthe medium(Fig. 2).During thepassageinto the tissue, in normal conditions the decrease in oxygen saturation is associated with binding of H + to hemoglobin. This effect (Haldane) ‘buffers’ in part the acid-base changes induced by the addition of VCO 2 from the tissue. The overall pictureis dramaticallychanged when a strong ion, such as lactate, is added from the tissue to venous blood. In this case, part of the [H + ] increase due to the increase of the strong ion lactate, is buffered by HCO 3 – which ‘liberates’ dissolved CO 2 (PvCO 2 ) according to the following reaction: Added H + + HCO 3V – → CO 2V + H 2 O Indeed for a given venous CO 2 content, adding acid sharply increases the PvCO 2 . The phenomenon is quite clear if we consider the CO 2 dissociation curve, at different BE, as shown in Figure 2. For the same CO 2 content, the change in BE Fig. 2. CO 2 dissociation curve. CO 2 content (ml % of whole blood) vs. CO 2 tension (PCO 2 ). Each curve is described at constant base excess (BE). As shown, for the same CO 2 content, changing the base excess causes a great change in PCO 2 (see the broken line parallel to axes). ‘Adequate’ Hemodynamics: A Question of Time? 77 (i.e., the addition of strong ions such as lactate) results in a great change in PCO 2 . Indeed, the large increase in venous PCO 2 during critical hypoxia (or during mitochondrial dysfunction) is not the result of the increased anaerobic VCO 2 production but instead of the acidity change induced (for a given CO 2 content) by the added strong ion. Due to the increased PvCO 2 , the expired CO 2 may tran- siently increase, before the new steady state is reached. This transient increase in expired CO 2 must not be confused with the VCO 2 metabolic production. Exhaled CO 2 equals the metabolic CO 2 production only at steady state. The increase in PvCO 2 is a very strong signal, and this is a reason why it has been proposed as a ‘useful marker’ of hypoxia [44, 45]. The distinction between content and tension helps to explain some of the contradictory findings in the theoretical and experi- mental literature [46]. Hemodynamic Adequacy in the Clinical Scenario As discussed above, the energy failure due to hemodynamic failure, to mitochon- drial dysfunction, or both, implies an adaptive response which consists of in- creased glycolysis (increased lactate, decreased BE, acidosis, and increased PvCO 2 ) associated with a relative dumping of the energy expenditure (oxygen conformance, i.e., VO 2 /DO 2 dependency). The distinction between hemodynamic inadequacy and mitochondrial dysfunction, either due to direct insult (primitive dysfunction) [47–50] or to mitochondrial structural disruption due to prolonged hypoxia (secondary dysfunction), may be clinically relevant. In fact, aggressive hemodynamic treatment is useless and potentially dangerous if the energy failure derives from mitochondrial dysfunction and not from inadequate hemodynamic status. To roughly discriminate between the two causes of energy failure (beside the baseline S V O 2 , low in hemodynamic failure), two challenge tests are available: the volume load and the dobutamine tests. Thefirst does not imply, per se, an increased oxygen consumption [51], and the second may contribute to an increased energy expenditure due to the direct thermogenic effects of dobutamine [52–57]. If the primary cause of the energy failure is tissue hypoxia due to inadequate hemody- namics and the volume infusion or the dobutamine test are able to increase the oxygen transport, the response should be an increased VO 2 (reduction of the adaptive response of oxygen conformity), and a decrease in lactate and its corre- lates (reduction of the adaptive response of increased anaerobic energy produc- tion). Such responses indicate that the mitocondrial function is still adequate. If the challenge test increases the oxygen transport but the VO 2 does not increase, this suggests that the mitochondria are unable to work properly either because of direct insult, as in sepsis, or because the hypoxia was so prolonged that the mitochondria were structurally impaired. 78 L. Gattinoni, F. Valenza, and E. Carlesso Volume Load Test This was the subject of two studies conducted by Haupt [58] and Gilbert [59]. The entry criteria (sepsis and circulatory failure), treatment (fluid load), and results were similar. In both studies, some patients were experiencing energy failure (as indicated by increased blood lactate levels). Of these, a subset responded to vol- ume challenge with an increase in DO 2 and VO 2 , indicating, from an energy point of view, oxygen supply dependency (oxygen conformance) and still adequate mitochondrial function. On the contrary, other patients with energy failure (high lactate) were unable to increase DO 2 while VO 2 did not significantly change or even decreased. A volume load test alone does not allow the discrimination in these patients between pump failure (cardiac failure) or a primary oxygen ma- chinery defect (mitochondrial failure). To discriminate between these two possi- ble mechanisms of hemodynamic inadequacy, a dobutamine test may be of use. Dobutamine Test In patients with energy failure (high lactate), a controlled infusion of dobutamine may reveal cardiac pump failure either when patients are hemodynamically stable [60] or not responsive to volume load [61]. An increased VO 2 , following an increased DO 2 , suggests that the oxygen machinery (mitochondria) is still func- tioning adequately. More complex is the interpretation of the test in septic patients without energy failure (normal lactate). Several studies have included these patients [60, 62–65]. Vallet [63] and Rhodes [65] prospectively tested the dobutamine response, strati- fying between patients that were able (responders) or not able (non-responders) toincreaseVO 2 by more than 15%of the baselinevalue. They found that responders showed a much greater increase in DO 2 than non-responders, and had a lower mortality. Since the patients were not in energy failure (normal lactate), it is difficult to hypothesize a ‘masked oxygen debt’, which is just an adaptive response (oxygen conformance) to the energy failure. It is possible that the responders had just a physiological response to the increased metabolic requirements due to the dobutamine. Indeed these patients had adequate hemodynamic response and adequate mitochondrial function. The non-responders, on the contrary, were not able to cope with the increased oxygen demand due to the dobutamine, suggesting both an inadequacy of hemodynamics and/or an inadequacy of mitochondrial function. In fact, considering the dobutamine test as an ‘increased energy demand challenge’, the non-responders developed energy failure with its typical responses (oxygen conformance and anaerobic metabolism) [63]. ‘Adequate’ Hemodynamics: A Question of Time? Based on the observation that survivors of high risk operations had significantly higher mean cardiac index, DO 2 , and VO 2 than non-survivors [66], and on the results of a prospective trial in which supranormal hemodynamic values used as a ‘Adequate’ Hemodynamics: A Question of Time? 79 therapeutic goal were associated with improved outcome [1], several studies have been conducted on the so called ‘hemodynamic optimization’. After more than 20 years, the matter is still debated. Two recent meta-analyses provided different conclusions [67, 68]. However, a few points must be stressed. First, most studies were targeted to increased DO 2 . From what we have discussed so far, it is quite evident that the crucial issue is not a given value of DO 2 but instead an oxygen supply sufficient to match the energy needs. Only two studies [69, 70] investigated a different target, i.e., a ‘normal’ SvO 2 , which more closely reflects the relationship between oxygen demand and supply. These two studies led to different results. Considering all the studies together, the difficulty in comparing them is quite evident. The study populations were different (high risk surgical patients, trauma patients, sepsis patients, etc.). The time of intervention was also not comparable (perioperative, in the emergency room, and in the intensive care unit [ICU]). Moreover, we do not know how many of the treated patients were at risk of energy failure and how many of them were actually in energy failure. It is beyond the scope of this chapter to attempt any detailed analysis of this controversialmatter, however we wouldlike tofocuson thetiming of interventions. As we discussed above, the adaptive responses to the energy failure (anaerobic energy production and oxygen conformance) are not long-standing mechanisms. It is likely that early interventions may reverse the energy failure more than interventions performed later, when the mitochondria are structurally impaired. Figure 3 shows, on an ideal time axis, three prototypical randomized controlled trials on hemodynamic treatment. In the study by Shoemaker et al., patients were investigated perioperatively [1]; the study by Rivers et al. was conducted on septic patients very early in the emergency room [69]; while that by Gattinoni et al. was a late study conducted on a general ICU population [70]. The main results are presented trying to focus the attention of the reader on time. As shown from the above mentioned meta-analysis [68], the earlier the intervention and the greater the physiological response to treatment, the better the outcome. If one could imagine a cell under impending energy failure, it becomes obvious that the earlier a clinician can correct a possible underlying hemodynamic failure, the greater the likelihood of the cell not to suffer from hypoxia or any insult originating from mediators. Therefore, time is the essence.We believethat this isclearly shown bycomparing our study of SvO 2 targeted treatment and the study by Rivers et al. The baseline SvO 2 of Rivers’ patientsin the emergency room was 49% [69]; this strongly suggests that their septic patients had an associated severe hemodynamic impairment. The early correction of the VO 2 /DO 2 mismatch (SvO 2 target 70%) was associated with a remarkable decrease in the blood lactate levels, suggesting that the treatment was able to reverse, at least in part, the energy failure. In our study [70], the patients were treated later in the ICU and their SvO 2 at entry was already close to the target (68%, with the target of 70%). Indeed all our hemodynamic manipulations were in the patients in whom most of the possible hemodynamic failure had already been corrected. It is then possible that when we started to treat the patients the game was already ‘over’. Of note, however, the tremendous importance of the hemodynamic status in the course of the disease, as shown in Figure 4. The patients who were not able to reach a normal SvO 2 had very high mortality rates. 80 L. Gattinoni, F. Valenza, and E. Carlesso Fig. 3. Results of three prototypical studies on hemodyamic treatment in critically ill patients, synopti- cally presented under a ‘time’ frame. ER: emergency room;ICU:intensivecareunit;CI:cardiacindex (ml/min/m 2 ); VO 2 : oxygen consumption (ml/min/m 2 ); DO 2 : oxygen delivery (ml/min/m 2 ); SvO 2 :venousoxygen saturation (%); CVP: central venous pressure (mmHg); *significant difference between treatments ‘Adequate’ Hemodynamics: A Question of Time? 81 Conclusion Energy failure is a life threatening condition. Energy failure induces two adaptive responses: oxygen conformance (i.e., a decrease in energy expenditure due to partial metabolic shut-down) and increased anaerobic energy production (i.e., increased lactate and acidosis). Energy failure may occur because of primitive mitochondrial impairment or insufficient oxygen supply (inadequate hemody- namics). This condition, if prolonged long enough, unavoidably leads to secon- dary mitochondrial failure. In patients, the prevalent mechanism of energy failure may be roughly assessed by considering the SvO 2 (low SvO 2 suggests tissue hy- poxia with adequate mitochondrial function). A volume load test and dobutamine challenge may also be of value in discriminating these two conditions. Early treatment to correct hemodynamic failure, before secondary irreversible mito- chondrial damage occurs, is likely associated with improved survival. Time is essential. References 1. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS (1988) Prospective trial of supra- normal values of survivors as therapeutic goals in high-risk surgical patients. Chest 94:1176–1186 Fig. 4. Sub-analysis of the SvO 2 study [70]. Percent mortality as a function of the percent of time that the patients maintained the target (SvO 2 >= 70%) during the 5-day study. 0% = never on target, i.e., SvO 2 always below 70%, 100% = patients always on target (SvO 2 >= 70%). 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